Vitamin B12 Deficiency

Deficiency of cobalamin, an essential cofactor for DNA synthesis (via methionine synthase) and for the conversion of methylmalonyl-CoA to succinyl-CoA in fatty acid metabolism, producing both haematological (megaloblastic anaemia) and neurological consequences, the latter of which can occur independently of and precede anaemia.

Causes

• Pernicious anaemia: autoimmune destruction of gastric parietal cells (and loss of intrinsic factor production), the classical cause in Western populations, associated with other autoimmune disease and a modestly increased gastric cancer risk.
• Dietary insufficiency: strict vegans, since B12 is found only in animal products; body stores typically last years, so deficiency develops slowly.
• Malabsorption: post-gastrectomy or bariatric surgery, terminal ileal disease/resection (Crohn disease, the site of B12-intrinsic factor complex absorption), coeliac disease, chronic pancreatitis (reduced pancreatic protease needed to release B12 from R-proteins), bacterial overgrowth (bacterial consumption of B12).
• Drugs: metformin (reduces absorption with long-term use), proton pump inhibitors and H2 antagonists (reduce acid-dependent release of B12 from food), nitrous oxide (oxidises and inactivates B12, particularly dangerous in those with marginal stores or undiagnosed deficiency, causing acute severe neurological injury).
• Fish tapeworm (Diphyllobothrium latum) infestation, competing for dietary B12.

• Fatigue, pallor, dyspnoea from anaemia, developing insidiously.
• Glossitis (smooth, sore, beefy red tongue) and angular cheilitis.
• Mild jaundice from ineffective erythropoiesis (intramedullary haemolysis), giving a lemon-yellow tinge to skin.
• Neurological manifestations, which can occur without anaemia and are the most clinically urgent aspect: subacute combined degeneration of the spinal cord (demyelination of dorsal columns and corticospinal tracts) presenting with symmetric peripheral neuropathy (numbness, paraesthesia, particularly in the feet), impaired proprioception and vibration sense, ataxia, spasticity and upgoing plantars, and in severe cases paraplegia.
• Cognitive changes: irritability, memory impairment, depression, and in severe cases dementia or psychosis ("megaloblastic madness"), potentially reversible with treatment if caught early.
• Autonomic and optic nerve involvement in severe cases.
• Pernicious anaemia specifically: associated autoimmune conditions (thyroid disease, vitiligo, type 1 diabetes), and a family history of autoimmune disease.

• Full blood count: macrocytic anaemia (MCV often markedly elevated, over 110), though may be normocytic early or if iron deficiency coexists.
• Blood film: hypersegmented neutrophils (6 or more lobes), oval macrocytes.
• Serum B12 level, recognising limitations: can be falsely normal in early or mild deficiency, and falsely low in pregnancy or with certain conditions without true deficiency.
• Where B12 is borderline or clinical suspicion is high despite a "normal" level, check methylmalonic acid (elevated in B12 deficiency specifically, not folate deficiency) and homocysteine (elevated in both B12 and folate deficiency) as more sensitive functional markers.
• Intrinsic factor antibodies (specific but insensitive for pernicious anaemia) and parietal cell antibodies (sensitive but less specific).
• Investigate the cause: coeliac serology, assessment of terminal ileal disease where relevant, medication review (metformin, proton pump inhibitors), dietary history, and consideration of upper gastrointestinal endoscopy in pernicious anaemia given gastric cancer risk.
• Always check folate simultaneously, since combined deficiency is common and treating B12 deficiency alone with folic acid can precipitate or worsen neurological injury by "unmasking" folate-driven haematological correction while cobalamin-dependent neurological damage progresses --- the key rule is never give folic acid alone when B12 deficiency is possible without first replacing or co-administering B12.

• Parenteral replacement is standard, particularly where malabsorption or neurological involvement is present: hydroxocobalamin 1mg intramuscularly, given as a loading course (typically alternate days for 2 weeks, or more frequently/for longer with neurological involvement --- sometimes every 2 days until no further improvement, which may take months) followed by maintenance injections (1mg every 2-3 months, lifelong if the underlying cause is not reversible, such as pernicious anaemia or permanent ileal loss).
• High-dose oral B12 (1000-2000 micrograms daily) is an effective alternative in some guidelines even for pernicious anaemia, given passive absorption independent of intrinsic factor accounts for roughly 1% of an oral dose, which is sufficient at high doses; parenteral remains preferred where adherence, absorption or severity is a concern, particularly with neurological disease.
• Monitor haematological response (reticulocyte rise within days, haemoglobin normalisation over weeks) and neurological response, which is slower and may be incomplete if treatment is delayed, particularly with longstanding subacute combined degeneration.
• Concurrent folate deficiency should be corrected together with, never before, B12 in cases of uncertain or combined deficiency.
• Monitor and replace potassium in the first week of treatment in severely deficient patients, since the marked erythropoietic response can precipitate hypokalaemia.
• Dietary counselling and consideration of prophylactic supplementation in strict vegans.
• Manage the underlying cause where identifiable and reversible (treat coeliac disease, bacterial overgrowth, review causative medications).
• In pernicious anaemia, note the association with other autoimmune disease and the modestly increased gastric malignancy risk, warranting a low threshold for endoscopy with new or alarm gastrointestinal symptoms.